|ZFIN ID: ZDB-PUB-200308-5|
MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool
Scaletti, E.R., Vallin, K.S., Bräutigam, L., Sarno, A., Berglund, U.W., Helleday, T., Stenmark, P., Jemth, A.S.
|Source:||The Journal of biological chemistry 295(15): 4761-4772 (Journal)|
|Registered Authors:||Braeutigam, Lars, Helleday, Thomas|
|Keywords:||MutT homologue 1 (MTH1), N6-methyl-dATP, Nudix hydrolase 1 (NUDT1), X-ray crystallography, crystal structure, enzyme catalysis, enzyme kinetics, epigenetics, hydrolase, methylation, nucleoside/nucleotide metabolism, nucleotide hydrolysis, substrate specificity|
|PubMed:||32144205 Full text @ J. Biol. Chem.|
Scaletti, E.R., Vallin, K.S., Bräutigam, L., Sarno, A., Berglund, U.W., Helleday, T., Stenmark, P., Jemth, A.S. (2020) MutT homologue 1 (MTH1) removes N6-methyl-dATP from the dNTP pool. The Journal of biological chemistry. 295(15):4761-4772.
ABSTRACTMutT homologue 1 (MTH1) removes oxidized nucleotides from the nucleotide pool and thereby prevents their incorporation into the genome and thereby reduces genotoxicity. We previously reported that MTH1 is an efficient catalyst of O6-methyl-dGTP hydrolysis suggesting that MTH1 may also sanitize the nucleotide pool from other methylated nucleotides. We here show that MTH1 efficiently catalyzes the hydrolysis of N6-methyl-dATP to N6-methyl-dAMP and further report that N6-methylation of dATP drastically increases the MTH1 activity. We also observed MTH1 activity with N6-methyl-ATP, albeit at a lower level. We show that N6-methyl-dATP is incorporated into DNA in vivo, as indicated by increased N6-methyl-dA DNA levels in embryos developed from MTH1 knock-out zebrafish eggs microinjected with N6-methyl-dATP compared with noninjected embryos. N6-methyl-dATP activity is present in MTH1 homologues from distantly related vertebrates, suggesting evolutionary conservation and indicating that this activity is important. Of note, N6-methyl-dATP activity is unique to MTH1 among related NUDIX hydrolases. Moreover, we present the structure of N6-methyl-dAMP-bound human MTH1, revealing that the N6-methyl group is accommodated within a hydrophobic active-site sub-pocket explaining why N6-methyl-dATP is a good MTH1 substrate. N6-methylation of DNA and RNA has been reported to have epigenetic roles and to affect mRNA metabolism. We propose that MTH1 acts in concert with adenosine deaminase-like protein isoform 1 (ADAL1) to prevent incorporation of N6-methyl-(d)ATP into DNA and RNA. This would hinder potential dysregulation of epigenetic control and RNA metabolism via conversion of N6-methyl-(d)ATP to N6-methyl-(d)AMP, followed by ADAL1 catalyzed deamination producing (d)IMP that can enter the nucleotide salvage pathway.